Processes for the synthesis of 5-(3-[exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydr opyrimidin-2(1H)-one

ABSTRACT

This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)3,4,5,6 tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.

The present application is a 371 of PCT/IB95/00319, filed May 4, 1995which is a CIP of U.S. application Ser. No. 08/286,579, filed Aug. 5,1994, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel processes for preparing thepharmaceutically active compound5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)3,4,5,6tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer andfor preparing certain intermediates used in the synthesis of thesecompounds. It also relates to novel intermediates used in the synthesisof such pharmaceutically active compounds and to other novel compoundsthat are related to such intermediates.

International Patent Application WO 87/06576, which was published onNov. 5, 1987, refers to5-(3-[(2-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6tetrahydropyrimidin-2(1H)-one,and states that it is useful as an antidepressant. International PatentApplication WO 91/07178, which was published on May 30, 1991, refers tothe utility of this compound in the treatment of asthma, inflammatoryairway diseases and skin diseases.

U.S. Pat. No. 5,270,206, which issued on Dec. 14, 1993, refers to aprocess for preparing (+)-(2R)-endo-norbomeol (also referred to as(2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S, 2R,4R)-bicyclo[2.2.1]heptan-2-ol) and (-)-(2S)-endo-norborneol (alsoreferred to as (2S)-endo-bicyclo[2.2.1]heptan-2-ol or (1R, 2S,4S)-bicyclo[2.2.1]heptan-2-ol), and to their further conversion into thepharmaceutically active agents5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one,depicted below, ##STR1## and5-(3-[(2R-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one,depicted below, ##STR2##

All documents cited herein, including the foregoing, are incorporatedherein by reference in their entireties.

SUMMARY OF THE INVENTION

This invention relates to a compound having the formula ##STR3## whereinX and Y are the same and are selected from --CN, --CO₂ (C₁ -C₆)alkyl,--CONH₂ and --CONHOH, or X and Y, taken together, form a group of theformula ##STR4##

This invention also relates to a compound having the formula ##STR5##wherein R¹ and R² are independently selected from (C₁ -C₆)alkyl andhydrogen.

This invention also relates to compounds of the formulae ##STR6##wherein each R² is independently selected from (C₁ -C₆) akyl.

This invention also relates to a process for preparing a compound of theformula ##STR7## wherein X and Y are the same and are selected from--CN, --CO₂ (C₁ -C₆)alkyl, --CONH₂ and --CONHOH, or X and Y, takentogether, form a group of the formula ##STR8## comprising: (1) reacting3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH₂ CO₂H, wherein X is defined as above, in the presence of a base, preferablya tertiary amine, to yield a compound of the formula II wherein X and Yare both --CN, --CO₂ (C₁ -C₆)alkyl, --CONH₂ or --CONHOH; or (2) (a)reacting a compound of the formula II wherein X and Y are both --CN withhydrogen peroxide, preferably basic aqueous hydrogen peroxide, to formthe corresponding bis-amide in which both --CN groups are replaced by--CONH_(2;) (b) subjecting the bis-amide formed in step (a) to a Hoffmanrearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene,bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) toform the corresponding biscarbamate; and (c) reacting the biscarbamateformed in step (b) with a base (e.g., an alkali metal alkoxidecontaining from one to six carbon atoms or an alkali metal hydroxide),to form a cyclic urea wherein X and Y, taken together, form a group ofthe formula "a", as depicted above.

This invention also relates to a process for preparing a compound of theformula ##STR9## wherein X and Y are defined as for formula II above,comprising reacting a compound of formula II, as defined above, with,respectively, R-(+)-endo-norbomeol or S-(-)-endo-norbomeol, a triaryl ortrialkyl phosphine and an azo dicarboxylate.

This invention also relates to a process for preparing a compound of theformula ##STR10## wherein X and Y are the same and are selected from--CN, --CONH₂, CO₂ (C₁ -C₆)alkyl and --CONHOH, or X and Y, takentogether, form a group of the formula ##STR11## comprising: (1) reacting3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH₂ CO₂H, wherein X is --CN, --CO₂ (C₁ -C,₆)alkyl, -CONH₂ or --CONHOH, in thepresence of a base, preferably a tertiary amine, to form a compound ofthe formula ##STR12## wherein X and Y are the same and are selected from--CN, --CONH₂, --CO(C₁ -C₆)alkyl and --CONHOH; or (2) (a) reacting acompound of the formula II wherein X and Y are both --CN with hydrogenperoxide to form the corresponding bis-amide in which both --CN groupsare replaced by --CONH₂ ; (b) subjecting the bis-amide formed in step(a) to a Hoffman rearrangement using an oxidizing agent (e.g.,bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBror lead tetraacetate) to form the corresponding biscarbamate; and (c)reacting the biscarbamate formed in step (b) with a base (e.g., analkali metal alkoxide containing from one to six carbon atoms), to forma cyclic area wherein X and Y, taken together, form a group of theformula ##STR13## and then (3) reacting said compound of formula II soformed in step 1 or 2 above with, respectively, R-(+)-endo-norbomeol orS-(-)-endo-norborneol, a triaryl or trialkyl phosphine and an azodicarboxylate.

This invention also relates to a process for preparing a compound of theformula ##STR14## wherein R¹ and R² are independently selected fromhydrogen and (C₁ -C₆)alkyl, comprising reacting, respectively, acompound of the formula ##STR15## with diacetoxyiodobenzene, NaOZ andZ'OH, wherein Z and Z' are independently selected from hydrogen and (C₁-C₆)alkyl.

This invention also relates to a process for preparing a compound of theformula ##STR16## comprising reacting, respectively, a compound of theformula ##STR17## wherein R¹ and R² are independently selected fromhydrogen and (C₁ -C₆)alkyl with compounds of the formulae NaOZ and Z'OH,wherein Z and Z' are independently selected from hydrogen and (C₁-C₆)alkyl.

This invention also relates to a process for preparing a compound of theformula ##STR18## comprising:

reacting, respectively, a compound of the formula ##STR19## withdiacetoxyiodobenzene, NaOZ and Z'OH, wherein Z and Z' are independentlyselected from hydrogen and (C₁ -C₆)alkyl, to form an intermediate of theformula ##STR20## wherein R¹ and R² are independently selected fromhydrogen and (C₁ -C₆)alkyl; and then either

(b1) isolating said intermediate of formula V or V' and reacting it withcompounds of the formulae NaOZ and Z'OH, wherein Z and Z' are defined asabove; or

(b2) reacting said intermediate of formula V or V' in situ withcompounds of the formula NaOZ and Z'OH, wherein Z and Z' are defined asabove.

As used herein, the expression "reaction inert solvent" refers to asolvent which does not interact with starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product or products.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

Formulae II, and V and V' above include compounds identical to thosedepicted but for the fact that one or more hydrogen, carbon, nitrogen oroxygen atoms are replaced by radioactive or stable isotopes thereof.Such radiolabelled compounds are useful as research and diagnostic toolsin metabolism pharmacokinetic studies and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION

The processes of the this invention and methods of preparing the novelcompounds of this invention are described in the following reactionschemes and discussion. Unless otherwise indicated, the substituents X,Y, R, R¹, R², R³, and R⁴, group "(a)" and formulae II, III, III', IV,IV', V, V', VI and VI' in the reaction schemes and discussion thatfollow are defined as above. ##STR21##

Scheme 1 illustrates the preparation of compounds of the formulae II andIII. Scheme 2 illustrates the preparation of compounds of the formula Vand also the preparation of5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-,4,5,6-tetrahydropyrimidin-2-(1H)-one(compound VI) from the compound of formula II wherein X and Y are both--CN. (Such compound of formula II wherein X and Y are both --CN isreferred to in scheme 2 and hereinafter as the compound of formulaIIIA.) Scheme 3 illustrates the preparation of compound VI fromcompounds of the formula III wherein X and Y are both --CO₂ (C₁-C₆)alkyl or --CONHOH. (The compound of formula III wherein X and Y areboth --CO₂ (C₁ -C₆)alkyl or --CONHOH are referred to in scheme 3 andhereinafter, respectively, as the compound of formula IIIB or IIIC).

Referring to scheme 1, isovanillin (compound 1) is condensed with twomolar equivalents of a compound of the formula XCH₂ CO₂ H, wherein X is--CN, --CO₂ (C₁ -C₆)alkyl, --CONH₂ or --CONHOH, in a sequentialKnoevenagel-Michael sense with accompanying decarboxylation, to yield acompound of the formula II, wherein X and Y are the same and areselected from the values given in the above definition of X, in areaction inert solvent in the presence of a base, preferably a tertiaryamine. This reaction may be conducted at a temperature ranging fromabout 10° C. to about 130° C. It is preferably conducted at about thereflux temperature. Suitable solvents include but are not limited toN-methylmorpholine, triethylamine, pyridine, as well as non-basicreaction-inert solvents such as tetrahydrofuran (THF), dimethylformamide(DMF), acetonitrile and toluene. Preferably, a secondary amine (e.g.,piperidine or pyrrolidine) is also added as a catalyst. In one preferredembodiment of the reaction, N-methylmorpholine is used as thesolvent/base and piperidine is also added to the reaction mixture.

Compounds of the formula II wherein X and Y, taken together, form agroup of the "a" (ie., the cyclic urea) may be prepared by subjectingthe compound of formula II wherein X and Y are both --CN to the seriesof reactions illustrated in scheme 2 and described later in thisapplication.

The compound of formula II formed in the above reaction can be convertedinto the corresponding compound of the formula III by coupling it underMitsunobu conditions with either R-(+)-endo-norborneol, depicted below,##STR22## or S-endo-norbomeol, depicted below ##STR23## to yield,respectively, the corresponding compound of formula III or III' havingthe opposite stereochemistry as determined by the endo-norbomeolreactant. Thus, if R-endo-norbomeol is used, the product will be acompound of the formula III that has an "S" configuration, and ifS-endo-norborneol is used, the product will be a compound of the formulaIII' that has an "R" configuration.

This reaction is typically carried out in the presence of a triaryl ortrialkyl phosphine such as triphenylphosphine or tributylphosphine andan azo dicarboxylate oxidizing agent. It is also generally carried outin an aprotic solvent such as tetrahydrofuran (THF) acetonitrile,methylene chloride, DMF, toluene and benzene, preferably THF, at atemperature from about 10° C. to about 150° C., preferably at about thereflux temperature. Suitable azo compounds includediisopropylazodicarboxylate, azodicarbonyldipiperldine anddiethylazodicarboxylate. Diisopropylazodicarboxylate andazodicarbonyidipiperidine are preferred.

The stereochemistry of the compound of formula III or III' formed in theabove step is retained in all subsequent steps shown in schemes 2 and 3.

As indicated above, scheme 2 illustrates the conversion of compounds ofthe formula IIIA into compounds of the formula VI. Referring to scheme2, a compound of the formula IIIA is hydrolyzed with hydrogen peroxide,preferably basic aqueous hydrogen peroxide, to form the bis-amide offormula IV. This reaction is typically conducted in a polar solvent suchas acetone, ethanol, isopropanol or methyl ethyl ketone, with acetonebeing preferred, at atemperature from about 0° C. to about 100° C., withabout room temperature being preferred. Sodium carbonate or anotherinorganic salt of similar basicity may be added to the reaction mixtureto accelerate the reaction.

The compound of formula IV so formed is then subjected to a Hoffmanrearrangement reaction in which both carboxamide groups are converted,with migration of nitrogen, into the carbamate groups of formula V.Suitable oxidizing reagents include bis(acetoxy)iodobenzene,bis(trifluoroacetoxy)iodobenzene, NaOCl, NaOBr and lead tetracetate maybe used. Bis(acetoxy)iodobenzene is preferred. This reaction istypically carried out in the presence of a base. Whendiacetoxyiodobenzene is used, acceptable bases include alkali metalhydroxides and (C₁ -C₆)alkoxides. The reaction temperature may rangefrom about -20° C. to about 100° C., with from about 0° C. to about 25°C. being preferred. Examples of appropriate reaction-inert solvents are(C₁ -C₆)alkanols, THF, DMF and acetonitrile.

The final step in the sequence is the base catalyzed closure of thebiscarbamate of formula V to form the symmetrical pyrimidin-2-one offormula VI. This reaction may be carried out from about 0° C. to about100° C., and is preferably carried out at the reflux temperature.Suitable solvents include but are not limited to lower alcohols, withmethanol being preferred. Suitable bases include alkali metal alkoxidescontaining from one to six carbon atoms. The preferred base is sodiummethoxide.

Alternatively, the last two steps of the sequence may be accomplished ina combined fashion without the isolation of the bis-carbamate V. Thismodification is essentially identical to the previous description of theHoffman rearrangement. It is preferable to conduct the reaction at thereflux temperature of the solvent. It is also preferable to addadditional base to the reaction mixture. The range of acceptableoxidizing agents, bases and solvents is the same as describedpreviously. The preferred reaction utilizes diacetoxyiodobenzene, sodiummethoxide and methanol.

The reaction of compounds of the formula V to form compounds of theformula VI, as described above, may proceed through one or both of theintermediates of formulae VII and VIII shown in scheme 2A.

The compound of formula III wherein X and Y are both --CONH₂ is the sameas the compound of formula IV, and therefore it can be converted intocompound (VI) using the methods Illustrated in scheme 2.

Compounds of the formula III wherein X and Y are both --CONHOH or --CO₂(C₁ -C₆)alkyl may be converted into compound VI using the methodsillustrated in scheme 3.

Referring to scheme 3, the diester of formula IIIB is reacted withhydroxylamine hydrochloride in the presence of a base, e.g., a tertiaryamine base, to form the hydroxamic acid of formula IIIC. This reactioncan be conducted in a variety of reaction-inert solvents that do nothave a strong nucleophilic character, including but not limited to loweralcohols, cyclic and acyclic ethers (e.g., ethyl ether or THF), neutralaromatic compounds such as benzene and toluene, DMF, dimethylacetamide,ethyl acetate, acetonitrile and water, at a temperature from about 0° C.to about 100° C., preferably at about 20° C.

The hydroxamic acid of formula IIIC can then be converted into compoundVI via a Loessen rearrangement using conditions or a reagent having theability to dehydrate an alcohol, at a temperature from about 0° to about100° C., preferably at about 20° C. The preferred reagent isp-toluenesulfonylchloride. Alternatively, one can form a different esterof the hydroxamic acid, optionally in situ, and then convert that estervia heat and/or acid treatment into the compound of formula VI, usingmethods well known in the art.

The preparation of other compounds of the present invention notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

In each of the reactions discussed or illustrated in the scheme above,pressure is not critical unless otherwise indicated. Pressures fromabout 0.5 atmospheres to about 3 atmospheres are generally acceptable,and ambient pressure, i.e., about 1 atmosphere, is preferred as a matterof convenience.

The processes and products of this invention are useful in the synthesisof the pharmaceutically active compounds VI and VI'. Compounds VI andVI', as well as racemic mixtures of these compounds (hereinafterreferred to, collectively as "the active compounds") are useful in thetreatment of depression, asthma, inflammatory airway disorders and skindisorders (e.g., psoriasis and atopic dermatitis).

The active compounds are calcium independent c-AMP phosphodiesteraseinhibitors. The ability of such compounds to Inhibit c-AMPphosphodiesterase may be determined by the method of Davis, Biochimicaet Biophysics. Acta., 797, 354-362 (1984).

The antidepressant activity of the active compounds may be determined bythe behavioral despair paradigm described by Porsult et al., Arch. Int.Pharmacodyn., 227, 327-336 (1977) and by the procedure described by Roeet at., J. Pharmacol. Exp. Therap., 226, 686-700 (1983) for determiningthe ability of a test drug to counteract reserpine hypothermia in mice.

When used for the treatment of depression the active compounds are usedas is or in the form of pharmaceutical compositions comprising an activecompound and pharmaceutically-acceptable carriers or diluents. For oraladministration, the preferred route for administering the activecompounds, suitable pharmaceutical carriers include inert diluents orfillers, thereby forming dosage forms such as tablets, powders,capsules, and the like. These pharmaceutical compositions can, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. For example, tablets containing variousexcipients, such as sodium citrate, are employed, together with variousdisintegrants such as starch, alginic acid and certain complexsilicates, together with binding agents such as polyvinylpyrrolidone,sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortabletting purposes. Solid compositions of a similar type may also beemployed as fillers in soft and hard filled gelatin capsules preferredmaterials therefor include lactose or milk sugar and high molecularweight polyethylene glycols.

For oral administration, the daily dose of active agent is from about0.1 mg to about 10 mg, and for parenteral administration, preferablyi.v. or i.m., from about 0.01 mg. to about 5 mg. The prescribingphysician, of course, will ultimately determine the appropriate dose fora given human subject dependent upon factors such as the severity of thepatient's symptoms and the patients response to the particular drug.

In vitro and in vivo tests relevant to the utility of the activecompounds in treating asthma and skin disorders are discussed inInternational Patent Application WO 91 /07178, referred to above andincorporated herein by reference in its entirety, on pages 4 and 5 ofthe specification and in Examples 1-3.

In the systemic treatment of asthma or inflammatory skin diseases withone of the active compounds, the dosage is generally from about 0.01 to2 mg/kg/day (0.5-100 mg/day in a typical human weighing 50 kg) in singleor divided doses, regardless of the route of administration. Of course,depending upon the exact compound and the exact nature of the individualillness, doses outside this range will be prescribed at the discretionof the attending physician. In the treatment of asthma, intranasal(drops or spray), inhalation of an aerosol through the mouth, andconventional oral administration are generally preferred. However, ifthe patient is unable to swallow, or oral absorption is otherwiseimpaired, the preferred systemic route of administration will beparenteral (i.m., i.v.). In the treatment of inflammatory skin diseases,the preferred route of administration is oral or topical. In thetreatment of inflammatory airway diseases, the preferred route ofadministration is intranasal or oral.

The active compounds are generally administered in the form ofpharmaceutical compositions comprising one of said compounds togetherwith a pharmaceutically acceptable vehicle or diluent. Such compositionsare generally formulated in a conventional manner utilizing solid orliquid vehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, powders and the like; forparenteral administration, in the form of injectable solutions orsuspensions, and the like; for topical administration, in the form ofsolutions, lotions, ointments, salves and the like, in generalcontaining from about 0.1 to 1% (w/v) of the active ingredient; and forintranasal or inhaler administration, generally as 0.1 to 1% (w/v)solution.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples.

EXAMPLE 1 3-(3-Hydroxy-4-methoxyphenyl)-pentane-1,5-dinitrile

To a 500 mL flask containing isovanillin (30.4 gm, 200 mmol) andcyanoacetic acid (68.0 gm, 800 mmol) was charged a solution consistingof 3.0 mL (30 mmol) piperidine and 151 mL N-methylmorpholine. Theinitially formed yellow slurry was warmed to mild reflux for 21 hoursand then cooled to room temperature and concentrated on a rotaryevaporator. The resulting brown oil was dissolved in 430 mL ethylacetate (EtOAc), washed sequentially with water (H₂ O), five normalhydrochloric acid (5N HCl) and H₂ O and the combined aqueous washes backextracted with dichloroethane. Combination of the organic layersfollowed by solvent removal led to a thick orange oil which wascrystallized from ethyl acetate/methylene chloride (EtOAc/CH₂ Cl₂) toyield 38.3 gm of orange solids after filtration and drying.Recrystallization from EtOAc/diisopropyl ether gave 35.3 gm (82%) oflight yellow solid, m.p. 90-92° C.

EXAMPLE 23-(3-[(2S)-exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-1,5-pentanedinitrile

To a tetrahydrofuran (THF) solution (20 mL) containingR-(+)-endo-norbomeol (1.12 gm, 10.0 mmol),3-(3-hydroxy-4-methoxyphenyl)-pentane-1,5-dinitrile (4.33 gm, 20 mmol)and triphenylphosphine (TPP) (3.93 gm, 15 mmol) was added1,1'-(azodicarbonyl)-dipiperldine (ADDP) (3.78 gm, 15 mmol) at roomtemperature. The resulting brown slurry was heated at reflux for 12hours, and then diluted with 10 mL THF and 30 mL toluene, cooled to roomtemperature and granulated for 30 minutes. After filtration to removethe reduced ADDP, the filtrate was washed 2X with 20 ml 1N sodiumhydroxide (NaOH) and the remaining organic phase stirred with 0.2 gmactivated charcoal and 20 gm sodium sulfate (Na₂ SO₄), filtered andconcentrated to a thick, dark brown oil. Recrystallization fromisopropanol/hexanes gave 2.34 gm (75%) of an off-white solid, m.p.126-127° C.

EXAMPLE 33-(3-[(2S)-exo-Biocyclo[2.2.]hept-2-yloxy]-4-methoxyphenyl)-pentane-1.5-dinitrile

To a refluxing solution of THF (30 mL) containing norbomeol (2.243 gm,20.00 mmol) and triphenylphosphine (5.272 gm, 20.10 mmol) was added asecond THF solution of3-(3-hydroxy-4-methoxyphenyl)-pentane-1,5-dinitrile (4.350 gm, 20.10mmol) and diisopropyl azodicarboxylate (DIAD) (4.044 gm, 21.00 mmol).The mixture was heated at reflux for 18 hours, cooled and concentratedon the rotary evaporator, and then redissolved in 60 mL toluene. Theresulting brown toluene solution was washed 2 times with 1N NaOH, driedover Na₂ SO₄, and filtered and concentrated to yield 18 gm of beigesolid. Recrystallization from 1/1 isopropanol/hexanes gave 4.26 gm (69%)of white solid, m.p. 127-128° C.

EXAMPLE 43-(3-[(2S)-exo-Bicyclo]2.2.1hept-2-yloxyl-4-methoxyphenyl)qlutaramide

To a cooled (6° C.) acetone solution (46 mL) of3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-pentane-1,5-dinitrile(2.29 gm, 7.38 mmol) was added 24 mL of 10% aqueous sodium carbonate(Na₂ CO₃) (23 mmol) followed by 5.2 mL of 30% hydrogen pyroxide (H₂ O₂).The resulting slurry was stirred at room temperature for 4 days, treatedwith an additional 1.7 mL 30% H₂ O₂ and then stirred for two more days.The excess peroxide was decomposed by the addition of 4 equivalents ofsodium bisulfite (NaHSO₃) and the volume was reduced to about 80 mL onthe rotary evaporator. The thick slurry was then acidified using 6.5 mLof concentrated HCl, neutralized with concentrated ammonium hydroxide(NH₄ OH) and condensed to about 50 mL of volume. Filtration and vacuumdrying provided 2.20 gm (86%) of white solids, m.p. 161-163° C.

EXAMPLE 55-(3-[(2S)-exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3.4.5.6-tetrahydropyrinidin-2(1H)-one

To a cooled (2°) methanol (MeOH) (40 mL) suspension ofdiacetoxyiodobenzene (43.60 gm, 133 mmol) was added 152 mL of 25% sodiummethoxide (NaOMe) in MeOH solution over 10 minutes. After stirring for20 minutes at 3° C.,3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)glutaramide(22.98 gm, 66.5 mmol) was added as a precooled slurry in 45 mL MeOH andthe reaction was allowed to warm to room temperature over 3 hoursfollowed by 45 minutes of heating at reflux. The slurry was cooled toroom temperature, treated with 152 mL of 25% NaOMe in MeOH solution andheated to reflux for 16 hours. The condenser was then replaced with adistillation head and 350 mL of MeOH was removed. The resulting slurrywas cooled to 12° C., diluted with 200 mL CH₂ Cl₂ and 100 ml H₂ O andneutralized with concentrated HCl. Separation of the layers andextraction of the aqueous layer 2X with CH₂ Cl₂ provided 3 organiclayers which were combined, dried over sodium sulfate (Na₂ SO₄),filtered and then concentrated to yield 39 gm of pale orange solid.Reslurry in refluxing EtOAc gave 15.48 gm of white solid (77%) m.p.199-200° C.

EXAMPLE 6N,N'-Dimethoxycarbonyl-2-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-1,3-propanediamine

To a cooled (0°C.) suspension of3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-glutaramide(0.346 gm, 1.00 mmol) in 1.75 ml of MeOH was added 0.140 gm of potassiumhydroxide (KOH) (2.50 mmol) followed by 0.657 gm (3.0 mmol)diacetoxyiodobenzene. The resulting hazy yellow solution was allowed towarm to room temperature, stir for 80 minutes and was then concentratedon the rotary evaporator to a paste. The material was transferred to aseparatory funnel with water and extracted two times with CH₂ Cl₂. Thecombined organic layers dried over Na₂ SO₄, filtered and concentrated toprovide 0.506 gm (125%) of the desired bis-carbamate as an impure yellowfoam. Thin layer chromatography (TLC): R₁ =0.74 in 9:1 CH₂ Cl₂ /MeOH.Gas chromatography--mass spectrometry showed the major peak with amolecular ion of 406 which is the molecular weight of the titlecompound.

EXAMPLE 75-(3[(2R)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one

The crude bis-carbamate foam from Example 6 (98 mg, 0.2 mmol) wasdissolved in MeOH (0.5 mL), treated with 0.5 mL of 25% NaOMe in MeOH,and refluxed for 18 hours. After removal of the solvent, the resultingsolid was dissolved in water, extracted two times with CH₂ Cl₂ and thecombined organic layers dried over magnesium sulfate (MgSO₄). Filtrationand concentration of the filtrate gave 48 mg (75%) of the desired ureaas a yellow solid. Thin layer chromatography (TLC): R₁ =0.57 in 9:1 CH₂Cl₂ /MeOH.

We claim:
 1. A process for preparing a compound of the formula ##STR24##comprising: (a) reacting, respectively, a compound of the formula##STR25## with diacetoxylodobenzene, NaOZ and Z'OH, wherein Z and Z'areindependently selected from hydrogen and (C₁ -C₆)alkyl, to form anintermediate of the formula ##STR26## wherein R¹ and R² areindependently selected from hydrogen and (C₁ -C₆)alkyl; and theneither:(b1) isolating said intermediate of formula V or V' and reactingit with compounds of the formulae NaOZ and Z'OH, wherein Z and Z' aredefined as above; or (b2) reacting said intermediate of formula V or V'in situ with compounds of the formula NaOZ and Z'OH, wherein Z and Z'are defined as above.
 2. A process for preparing a compound of theformula (VI) or (VI') (VI) ##STR27## comprising: (1) reacting3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH₂ CO₂H, wherein X is --CN, --CO₂ (C₁ -C₆)alkyl, --CONH₂ or --CONHOH, in thepresence of a base, to form a compound of the formula ##STR28## whereinX is as defined above; or (2) (a) reacting a compound of the formula II'wherein each X is --CN with hydrogen peroxide to form the correspondingbis-amide in which both --CN groups are replaced by --CONH₂ ; (b)subjecting the bis-amide formed in step (a) to a Hoffman rearrangementusing an oxidizing agent to form the corresponding biscarbamate; and (c)reacting the biscarbamate formed in step (b) with a base to form acyclic urea wherein X and X taken together forms a group of the formula##STR29## and then (3) reacting said compound of formula II' formed instep 1 or 2 above with a triaryl or trialkylphosphine, an azodicarboxylate, and either R-(+)-endo-norbomeol or S-(-)-endo-norborneol,respectively.
 3. A process according to claim 2 wherein said base is atertiary amine.
 4. A process according to claim 2 wherein both atertiary amine and a secondary amine are added to the reaction mixture.5. A process according to claim 4 wherein the tertiary amine is selectedfrom N-methylmorpholine, triethylamine, pyridine and diisopropyl amineand the secondary amine is selected from piperidine and pyrrolidine. 6.A process according to claim 2 wherein the azo dicarboxylate is selectedfrom diisopropylazadicarboxylate and azodicarbonyldipiperidine.
 7. Aprocess according to claim 2 wherein the triarylphosphine istriphenylphosphine.
 8. A process for preparing a compound of the formula##STR30## comprising reacting, respectively, a compound of the formula##STR31## wherein R¹ and R² are independently selected from hydrogen and(C₁ -C₆)alkyl, with compounds of the formulae NaOZ and Z'OH, wherein Zand Z' are independently selected from hydrogen and (C₁ -C₆)alkyl.
 9. Aprocess for preparing a compound of the formula ##STR32## wherein X andY, taken together, form a group of the formula. ##STR33## comprising:(a) reacting a compound of the formula II wherein X and Y are both --CNwith hydrogen peroxide to form the corresponding bis-amide in which both--CN groups are replaced by --CONH₂ ;(b) subjecting the bis-amide formedin step (a) to a Hoffinan rearrangement using an oxidizing agent to formthe corresponding biscarbamate; and (c) reacting the biscarbamate formedin step (b) with a base to form a cyclic urea wherein X and Y takentogether, form a group of the formula ##STR34##10.
 10. A processaccording to claim 9, wherein said base is a tertiary amine.
 11. Aprocess according to claim 9, wherein both a tertiary amine and asecondary amine are added to the reaction mixture.
 12. A processaccording to claim 11, wherein said secondary amine is piperidine orpyrrolidine.
 13. A process for preparing a compound of the formula.wherein X and Y, taken together, form a group of the formula ##STR35##comprising (a) reacting a compound of formula (II) ##STR36## wherein Xis --NHCOOR¹ and Y is --NHCOOR², where R¹ and R² are independentlyselected from (C₁ -C₆)alkyl or hydrogen, with a base to form a compoundof formula (II) wherein X and Y, taken together, form a group of theformula (a) above and(b) reacting the product of step (a) with a triarylor trialkylphosphine, an azo dicarboxylate and eitherR(+)-endo-norbomeol or S-(-)-endo-norbomeol, respectively.
 14. A processfor preparing a compound of the formula (VI) or (VI') ##STR37##comprising (a) reacting a compound of formula (II) ##STR38## wherein Xis --NHCOOR¹ and Y is --NHCOOR², where R¹ and R² are independentlyselected from (C₁ -C₆)alkyl or hydrogen, with a base to form a compoundof formula and (b) reacting said compound formed in step (a) above witha triaryl or trialkylphosphine, an azo dicarboxylate, and eitherR-(+)-endo-norborneol or (S)-(-)-endo-norborneol, respectively.